ABSTRACT The United States is at the forefront of the global obesity epidemic. To understand the mechanisms driving increases in obesity, this first cycle of the R01-DK099039 project developed and validated a novel laboratory model for overeating highly palatable (HP) foods in the context of HP food cue and stressful environments, both of which are associated with weight gain and obesity risk. Findings supported that BMI-related adaptations in cortisol, ghrelin, insulin sensitivity, HP food craving and hunger each predicted HP overeating in a Food Snack Test (FST) in a laboratory experiment, and remarkably, these measures also prospectively predicted weight gain over a longitudinal 2-year outcome period. Recent data suggests glucagon-like peptide-1 (GLP-1) modulates stress biology along with its effects on metabolism. Preliminary work by led by Dr. Jastreboff indicate GLP-1 analogue (GLP-1a) treatment decreases craving, hunger and food intake in both the laboratory and real-world setting. Thus, in this competitive renewal, we propose a multi-PI experimental therapeutics approach with the GLP-1a, semaglutide, in the unique and predictive laboratory model developed in the current project to test the hypothesis that GLP-1a treatment will attenuate HP food cue- and stress-induced food motivation and intake in obesity and also improve metabolic and stress responses and such changes will predict weight outcomes. A randomized, double-blind, placebo-controlled 12-week study with GLP-1a in men and women (N=96) with obesity (BMI 30-39.9 kg/m2) is proposed to test the above overall hypothesis both in a laboratory experiment and over a 12 -week treatment period to assess real-world outcomes. Specific aims are: 1) to examine the effects of GLP-1a vs. PBO treatment on food craving, hunger, food-cue- and stress- induced FST intake and eating topography in the FST; 2) to assess the effects of GLP-1a vs. PBO treatment on weekly food craving and food calorie intake in the real-world setting during the 12-week treatment period; and 3) to examine the effects of GLP-1a treatment on metabolic and stress responses (ghrelin, cortisol, and insulin resistance) on HP food craving and intake in the experimental lab model of food craving and FST intake. Exploratory aims will GLP-1a changes in laboratory outcomes predict weight outcomes and whether specific factors such as gender, chronic stress, disordered eating, diet and physical activity affect outcomes. Utilizing a novel experimental therapeutics approach, the next phase of this project will apply the current cycle?s validated laboratory model of identifying processes underlying greater HP food craving, intake and weight gain to test mechanisms by which a GLP-1a analogue exerts significant weight effects in obesity. Positive findings will not only inform how GLP-1a exerts effects on weight, but also provide a unique, stress and food cue sensitive, innovative and cost-effective human laboratory approach for testing novel therapeutics to decrease HP food craving, overeating and weight gain.